Azetidine, pyrrolidine and piperidine derivatives

ABSTRACT

A class of substituted azetidine, pyrrolidine and piperidine derivatives, linked by a fluoro-substituted alkylene chain to a fused bicyclic heteroaromatic moiety such as indolyl, are selective agonists of 5-HT 1  -like receptors, being potent agonists of the human 5-HT 1D α  receptor subtype while possessing at least a 10-fold selective affinity for the 5-HT 1D α  receptor subtype relative to the 5-HT 1D β  subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT 1D  receptors is indicated, while eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT 1D  receptor agonists.

This application is 371 of PCT/GB96/02764 filed Nov. 13, 1996, now WO97/18201, published May 22, 1997.

The present invention relates to a class of substituted azetidine,pyrrolidine and piperidine derivatives which act on 5-hydroxytryptamine(5-HT) receptors, being selective agonists of so-called "5-HT₁ -like"receptors. They are therefore useful in the treatment of clinicalconditions for which a selective agonist of these receptors isindicated.

It has been known for some time that 5-HT₁ -like receptor agonists whichexhibit selective vasoconstrictor activity are of use in the treatmentof migraine (see, for example, A. Doenicke et al., The Lancet, 1988,Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey, Drug DevelopmentResearch, 1992, 26, 235-240).

The human 5-HT₁ -like or 5-HT_(1D) receptor has recently been shown bymolecular cloning techniques to exist in two distinct subtypes. Thesesubtypes have been termed 5-HT_(1D)α (or 5-HT_(1D-1)) and 5-HT_(1D)β (or5-HT_(1D-2)), and their amino acid sequences are disclosed and claimedin WO-A-91/17174.

The 5-HT_(1D)α receptor subtype in humans is believed to reside onsensory terminals in the dura mater. Stimulation of the 5-HT_(1D)αsubtype inhibits the release of inflammatory neuropeptides which arethought to contribute to the headache pain of migraine. The human5-HT_(1D)β receptor subtype, meanwhile, is located predominantly on theblood vessels and in the brain, and hence may play a part in mediatingconstriction of cerebral and coronary arteries, as well as CNS effects.

Administration of the prototypical 5-HT_(1D) agonist sumatriptan(GR43175) to humans is known to give rise at therapeutic doses tocertain adverse cardiovascular events (see, for example, F. Willett etal., Br. Med. J., 1992, 304, 1415; J. P. Ottervanger et al., The Lancet,1993, 341, 861-2; and D. N. Bateman, The Lancet, 1993, 341, 221-4).Since sumatriptan barely discriminates between the human 5-HT_(1D)α and5-HT_(1D)β receptor subtypes (cf. WO-A-91/17174, Table 1), and since itis the blood vessels with which the 5-HT_(1D)β subtype is most closelyassociated, it is believed that the cardiovascular side-effects observedwith sumatriptan can be attributed to stimulation of the 5-HT_(1D)βreceptor subtype. It is accordingly considered (cf. G. W. Rebeck et al.,Proc. Natl. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which caninteract selectively with the 5-HT_(1D)α receptor subtype, whilst havinga less pronounced action at the 5-HT_(1D)β subtype, might be free from,or at any rate less prone to, the undesirable cardiovascular and otherside-effects associated with non-subtype-selective 5-HT_(1D) receptoragonists, whilst at the same time maintaining a beneficial level ofanti-migraine activity.

The compounds of the present invention, being selective 5-HT₁ -likereceptor agonists, are accordingly of benefit in the treatment ofmigraine and associated conditions, e.g. cluster headache, chronicparoxysmal hemicrania, headache associated with vascular disorders,tension headache and paediatric migraine. In particular, the compoundsaccording to this invention are potent agonists of the human 5-HT_(1D)αreceptor subtype. Moreover, the compounds in accordance with thisinvention have been found to possess at least a 10-fold selectiveaffinity for the 5-HT_(1D)α receptor subtype relative to the 5-HT_(1D)βsubtype, and they can therefore be expected to manifest fewerside-effects than those associated with non-subtype-selective 5-HT_(1D)receptor agonists.

Several distinct classes of substituted five-membered heteroaromaticcompounds are described in published European patent applications0438230, 0494774 and 0497512, and published International patentapplications 93/18029, 94/02477 and 94/03446. The compounds describedtherein are stated to be agonists of 5-HT₁ -like receptors, andaccordingly to be of particular use in the treatment of migraine andassociated conditions. None of these publications, however, disclosesnor even suggests the azetidine, pyrrolidine and piperidine derivativesprovided by the present invention.

In EP-A-0548813 is described a series of alkoxypyridin-4yl andalkoxypyrimidin-4-yl derivatives of indol-3-ylalkylpiperazines which arealleged to provide treatment of vascular or vascular-related headaches,including migraine. There is, however, no disclosure nor any suggestionin EP-A-0548813 of replacing the precisely substituted piperazine moietydescribed therein with a differently substituted azetidine, pyrrolidineor piperidine moiety; nor is there any suggestion therein that thealkylene chain present in the indol-3-ylalkylpiperazine portion of themolecule might be substituted with one or more fluorine atoms.

WO-A-91/18897 describes a class of tryptamine derivatives substituted byvarious five-membered rings, which are stated to be specific to aparticular type of "5-HT₁ -like" receptor and thus to be effectiveagents for the treatment of clinical conditions, particularly migraine,requiring this activity. A further class of tryptamine derivatives withalleged anti-migraine activity is disclosed in WO-A-94/02460. However,neither WO-A-91/18897 nor WO-A-94/02460 discloses or suggests theazetidine, pyrrolidine and piperidine derivatives provided by thepresent invention.

Moreover, nowhere in the prior art mentioned above is there anydisclosure of a subtype-selective 5-HT_(1D) receptor agonist having a5-HT_(1D)α receptor binding affinity (IC₅₀) below 50 nM and at least a10-fold selective affinity for the 5-HT_(1D)α receptor subtype relativeto the 5-HT_(1D)β subtype.

The compounds according to the present invention are subtype-selective5-HT_(1D) receptor agonists having a human 5-HT_(1D)α receptor bindingaffinity (IC₅₀) below 50 nM, typically below 10 nM and preferably below1 nM; and at least a 10-fold selective affinity, typically at least a50-fold selective affinity and preferably at least a 100-fold selectiveaffinity, for the human 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype. Moreover, the compounds in accordance with thisinvention possess interesting properties in terms of their efficacyand/or bioavailability.

The present invention provides a compound of formula I, or a salt orprodrug thereof: ##STR1## wherein Z represents hydrogen, halogen, cyano,nitro, trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂CONR⁵ R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶,--NR⁵ CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group offormula (Za), (Zb), (Zc) or (Zd): ##STR2## in which the asterisk *denotes a chiral centre; or Z represents an optionally substitutedfive-membered heteroaromatic ring selected from furan, thiophene,pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole,oxadiazole, thiadiazole, triazole and tetrazole;

X represents oxygen, sulphur, --NH-- or methylene;

Y represents oxygen or sulphur;

E represents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to6 carbon atoms, substituted in any position by one or more fluorineatoms;

T represents nitrogen or CH;

U represents nitrogen or C--R² ;

V represents oxygen, sulphur or N--R³ ;

R², R³ and R⁴ independently represent hydrogen or C₁₋₆ alkyl;

R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl, trifluoromethyl,phenyl, methylphenyl, or an optionally substituted aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl group; or R⁵ and R⁶, when linked through anitrogen atom, together represent the residue of an optionallysubstituted azetidine, pyrrolidine, piperidine, morpholine or piperazinering;

M represents the residue of an azetidine, pyrrolidine or piperidinering;

R represents a group of formula --W--R¹ ;

W represents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms, optionally substituted in anyposition by a hydroxy group;

R¹ represents --OR^(x), --SR^(x), --SOR^(x), --SO₂ R^(x) or --NR^(x)R^(y) ;

R^(x) and R^(y) independently represent hydrogen, hydrocarbon or aheterocyclic group; or R^(x) and R^(y) together represent a C₂₋₆alkylene group, which alkylene group may be optionally substituted byone or more substituents selected from C₁₋₆ alkyl, aryl and hydroxy, orfused with a phenyl ring; and

R^(a) represents hydrogen, hydroxy, hydrocarbon or a heterocyclic group.

Where Z in the compounds of formula I above represents a five-memberedheteroaromatic ring, this ring may be optionally substituted by one or,where possible, two substituents. As will be appreciated, where Zrepresents an oxadiazole, thiadiazole or tetrazole ring, only onesubstituent will be possible; otherwise, one or two optionalsubstituents may be accommodated around the five-membered heteroaromaticring Z. Examples of suitable substituents on the five-memberedheteroaromatic ring Z include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,heteroaryl, heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl.

When R⁵ and R⁶, when linked through a nitrogen atom, together representthe residue of an azetidine, pyrrolidine, piperidine, morpholine orpiperazine ring, this ring may be unsubstituted or substituted by one ormore substituents. Examples of suitable substituents include C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₂₋₆ alkoxycarbonyl and C₁₋₆alkylaminocarbonyl. Typical substituents include methyl, benzyl,methoxy, methoxycarbonyl, ethoxycarbonyl and methylaminocarbonyl. Inparticular, where R⁵ and R⁶ together represent the residue of apiperazine ring, this ring is preferably substituted on the distalnitrogen atom by a C₂₋₆ alkoxycarbonyl moiety such as methoxycarbonyl orethoxycarbonyl.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The term "hydrocarbon" as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl andaryl(C₁₋₆)alkyl.

The expression "a heterocyclic group" as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl and heteroaryl(C₁₋₆)alkylgroups.

Suitable alkyl groups include straight-chained and branched alkyl groupscontaining from 1 to 6 carbon atoms. Typical examples include methyl andethyl groups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl,isobutyl, tert-butyl and 2,2-dimethylpropyl.

Suitable alkenyl groups include straight-chained and branched alkenylgroups containing from 2 to 6 carbon atoms. Typical examples includevinyl, allyl and dimethylallyl groups.

Suitable alkynyl groups include straight-chained and branched alkynylgroups containing from 2 to 6 carbon atoms. Typical examples includeethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbonatoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Typical examples of C₃₋₇ cycloalkyl(C₁₋₆)alkyl groups includecyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

Particular indanyl groups include indan-1-yl and indan-2-yl.

Particular aryl groups include phenyl and naphthyl.

Particular aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolylgroups.

The expression "heteroaryl(C₁₋₆)alkyl" as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl,thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl andisoquinolinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionallysubstituted by one or more groups selected from C₁₋₆ alkyl, adamantyl,phenyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, trifluoromethyl,hydroxy, C₁₋₆ alkoxy, aryloxy, keto, C₁₋₆ alkylenedioxy, nitro, cyano,carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C₂₋₆ alkylcarbonyl,arylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl,arylsulphonyl, --NR^(v) R^(w), --NR^(v) COR^(w), --NR^(v) CO₂ R^(w),--NR^(v) SO₂ R^(w), --CH₂ NR^(v) SO₂ R^(w), --NHCONR^(v) R^(w),--CONR^(v) R^(w), --SO₂ NR^(v) R^(w) and --CH₂ SO₂ NR^(v) R^(w), inwhich R^(v) and R^(w) independently represent hydrogen, C₁₋₆ alkyl, arylor aryl(C₁₋₆)alkyl, or R^(v) and R^(w) together represent a C₂₋₆alkylene group.

When R^(x) and R^(y), or R^(v) and R^(w), together represent a C₂₋₆alkylene group, this group may be an ethylene, propylene, butylene,pentamethylene or hexamethylene group, preferably butylene orpentamethylene.

When R^(x) and R^(y) together represent a C₂₋₆ alkylene group, thisgroup may be unsubstituted or substituted by one or more substituentsselected from C₁₋₆ alkyl, aryl and hydroxy. Typical substituents includemethyl, phenyl and hydroxy.

Furthermore, when R^(x) and R^(y) together represent a C₂₋₆ alkylenegroup, this group may optionally be fused with a phenyl ring. In thiscontext, a typical group of formula --NR^(x) R^(y) as defined for thesubstituent R¹ is 1,2,3,4-tetrahydroisoquinolinyl.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. For example,the compounds of formula I above wherein Z represents a group of formula(Zb) or (Zc) have a chiral centre denoted by the asterisk *, which mayaccordingly be in the (R) or (S) configuration. It is to be understoodthat all such isomers and mixtures thereof in any proportion areencompassed within the scope of the present invention.

In particular, where M represents the residue of a pyrrolidine ring, andthe substituent R is attached to the 2-position thereof, then theabsolute stereochemical configuration of the carbon atom at the point ofattachment of the moiety R is preferably as depicted in structure IA asfollows: ##STR3## wherein Z, E, Q, T, U, V, R and R^(a) are as definedabove.

Moreover, where M represents the residue of a pyrrolidine ring, and thesubstituent R is attached to the 3-position thereof, then the absolutestereochemical configuration of the carbon atom at the point ofattachment of the moiety R is preferably as depicted in structure IB asfollows: ##STR4## wherein Z, E, Q, T, U, V, R and R^(a) are as definedabove.

Where E and W, which may be the same or different, represent straight orbranched alkylene chains, these may be, for example, methylene,ethylene, 1-methylethylene, propylene, 2-methylpropylene or butylene. Inaddition, W may be substituted in any position by a hydroxy group givingrise, for example, to a hydroxymethyl-methylene, 2-hydroxypropylene or2-hydroxymethyl-propylene linkage. Moreover, E and W may eachindependently represent a chemical bond. Where E represents a chemicalbond, the moiety Z is attached directly to the central fused bicyclicheteroaromatic ring system containing the variables T, U and V.Similarly, where W represents a chemical bond, the substituent R¹ isattached directly to the azetidine, pyrrolidine or piperidine ring ofwhich M is the residue.

Suitably, E represents a chemical bond or a methylene linkage.

The alkylene chain Q is substituted in any position by one or morefluorine atoms, preferably by one or two fluorine atoms and morepreferably by one fluorine atom. Representative alkylene chains for Qinclude 2-fluoropropylene, 2,2-difluoropropylene and2-fluoromethyl-propylene, especially 2-fluoropropylene or2-fluoromethyl-propylene.

The compound of formula I in accordance with the present invention issuitably an indole, benzofuran or benzthiophene derivative of formulaIC, an indazole derivative of formula ID, or a pyrrolo[2,3-c]-pyridinederivative of formula IE: ##STR5## wherein Z, E, Q, V, M, R, R^(a), R²and R³ are as defined above. Preferably, the compounds according to theinvention are indole or pyrrolo[2,3-c]-pyridine derivatives of formulaIF: ##STR6## wherein Z, E, Q, T, M, R, R^(a), R² and R³ are as definedabove, in particular wherein R² and R³ are both hydrogen.

Suitably, W represents a chemical bond or a methylene orhydroxymethyl-methylene linkage, in particular a chemical bond or amethylene linkage.

Suitably, R^(x) and R^(y) independently represent hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl,aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted by one or more substituentsselected typically from C₁₋₆ alkyl, halogen, hydroxy, C₁₋₆ alkoxy,aminocarbonyloxy, amino, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulphonylamino and C₁₋₆ alkylaminosulphonylmethyl. Particularvalues of R^(x) and R^(y) include hydrogen, methyl, hydroxyethyl,isobutyl, 2,2-dimethylpropyl, allyl, dimethylallyl, 1-cyclohexylethyl,2-cyclohexylethyl, indanyl, hydroxy-indanyl, phenyl, benzyl,methyl-benzyl, fluorobenzyl, methoxy-benzyl, acetylamino-benzyl,l-phenylethyl, 2-phenylethyl, 2-hydroxy-1-phenylethyl,2-methoxy-1-phenylethyl, 2-aminocarbonyloxy-1-phenylethyl,1-(fluorophenyl)ethyl, 1-(fluorophenyl)-2-hydroxyethyl,1-(fluorophenyl)-2-methoxyethyl, 1-(acetylamino-phenyl)ethyl,2-(acetylamino-phenyl)ethyl, 2-hydroxy-1-phenylprop-1-yl,1-phenylprop-2-yl, 2-phenylprop-2-yl, 1-hydroxy-1-phenylprop-2-yl,1-hydroxy-2-phenylprop-2-yl, 1-hydroxy-3-phenylprop-2-yl, furylmethyl,thienylmethyl and pyridylmethyl, especially hydrogen, methyl, benzyl or1-(fluorophenyl)-2-hydroxyethyl.

In addition, where R^(x) and R^(y) together represent an optionallysubstituted or phenyl ring-fused C₂₋₆ alkylene group, the substituent--NR^(x) R^(y) as defined for R¹ may suitably represent3,3-dimethylpiperidinyl, 2-phenylpiperidinyl,3-hydroxy-2-phenylpiperidinyl or 1,2,3,4-tetrahydroisoquinolin-2-yl.

Suitable values for the substituent R¹ include hydroxy, benzyloxy,methoxy-benzyloxy, pyridylmethoxy, benzylthio, fluorobenzyl-thio,phenylsulphinyl, benzylsulphinyl, fluorobenzyl-sulphinyl,fluorobenzyl-sulphonyl, amino, methylamino, indanylamino,hydroxyindanyl-amino, benzylamino, N-(methylbenzyl)-amino,N-(acetylamino-benzyl)-amino, N-(1-phenylethyl)-amino,N-(2-phenylethyl)-amino, N-(2-hydroxy-1-phenylethyl)-amino,N-(2-methoxy-1-phenylethyl)-amino,N-(2-aminocarbonyloxy-1-phenylethyl)-amino,N-[1-(fluorophenyl)ethyl]-amino,N-[1-(fluorophenyl)-2-hydroxyethyl]-amino,N-[1-(fluorophenyl)-2-methoxyethyl]-amino,N-[1-(acetylamino-phenyl)ethyl]-amino,N-[2-(acetylamino-phenyl)ethyl]-amino,N-(2-hydroxy-1-phenylprop-1-yl)-amino, N-(1-phenylprop-2-yl)-amino,N-(2-phenylprop-2-yl)-amino, N-(1-hydroxy-1-phenylprop-2-yl)-amino,N-(1-hydroxy-2-phenylprop-2-yl)-amino,N-(1-hydroxy-3-phenylprop-2-yl)-amino, N-(furylmethyl)-amino,N-(pyridylmethyl)-amino, dimethylamino, N-isobutyl-N-methylamino,N-(2,2-dimethylpropyl)-N-methylamino, N-allyl-N-methylamino,N-(3,3-dimethylprop-2-en-1-yl)-N-methylamino,N-(1-cyclohexylethyl)-N-methylamino, N-benzyl-N-methylamino,N-methyl-N-(methylbenzyl)-amino, N-(fluorobenzyl)-N-methylamino,N-(acetylamino-benzyl)-N-methylamino, N-methyl-N-(1-phenylethyl)-amino,N-methyl-N-(2-phenylethyl)-amino,N-(2-hydroxy-1-phenylethyl)-N-methylamino,N-(2-methoxy-1-phenylethyl)-N-methylamino,N-[2-(acetylamino-phenyl)ethyl]-N-methylamino,N-(furylmethyl)-N-methylamino, N-methyl-N-(thienylmethyl)-amino,N-benzyl-N-(2-hydroxyethyl)-amino, N,N-bis(furylmethyl)-amino,3,3-dimethylpiperidinyl, 2-phenylpiperidinyl,3-hydroxy-2-phenylpiperidinyl and 1,2,3,4-tetrahydroisoquinolin-2-yl.

Particular examples of R¹ include benzyloxy,N-[1-(fluorophenyl)-2-hydroxyethyl]-amino and N-benzyl-N-methylamino.

Representative values of the group R include hydroxy, benzyloxy,benzyloxymethyl, methoxy-benzyloxy, pyridylmethoxy, benzylthio-methyl,fluorobenzylthio-methyl, phenylsulphinylmethyl, benzylsulphinylmethyl,fluorobenzyl-sulphinyl, fluorobenzyl-sulphinylmethyl,fluorobenzyl-sulphonylmethyl, indanylamino, indanylaminomethyl,hydroxyindanyl-amino, benzylamino, benzylaminomethyl,1-(N-benzylamino)-2-hydroxyethyl, N-(methylbenzyl)-aminomethyl,N-(acetylamino-benzyl)-amino, N-(acetylamino-benzyl)-aminomethyl,N-(1-phenylethyl)-amino, N-(1-phenylethyl)-aminomethyl,N-(2-phenylethyl)-aminomethyl, N-(2-hydroxy-1-phenylethyl)-amino,N-(2-hydroxy-1-phenylethyl)-aminomethyl,N-(2-methoxy-1-phenylethyl)-amino,N-(2-aminocarbonyloxy-1-phenylethyl)-amino,N-[1-(fluorophenyl)ethyl]-amino,N-[1-(fluorophenyl)-2-hydroxyethyl]-amino,N-[1-(fluorophenyl)-2-methoxyethyl]-amino,N-[1-(acetylamino-phenyl)ethyl]-amino,N-[1-(acetylamino-phenyl)ethyl]-aminomethyl,N-[2-(acetylamino-phenyl)ethyl]-amino,N-(2-hydroxy-1-phenylprop-1-yl)-amino, N-(1-phenylprop-2-yl)-amino,N-(2-phenylprop-2-yl)-aminomethyl, N-(1-hydroxy-1-phenylprop-2-yl)-amino, N-(1-hydroxy-2-phenylprop-2-yl)-amino,N-(1-hydroxy-3-phenylprop-2-yl)-amino, N-(furylmethyl)-amino,N-(furylmethyl)-aminomethyl, N-pyridylmethyl)-aminomethyl,N-isobutyl-N-methyl-aminomethyl,N-(2,2-dimethylpropyl)-N-methyl-aminomethyl, N-allyl-N-methylamino,N-(3,3-dimethylprop-2-en-1-yl)-N-methylamino,N-(1-cyclohexylethyl)-N-methyl-aminomethyl, N-benzyl-N-methylamino,N-benzyl-N-methyl-aminomethyl, N-methyl-N-(methylbenzyl)-aminomethyl,N-(fluorobenzyl)-N-methylamino,N-(acetylamino-benzyl)-N-methyl-aminomethyl,N-methyl-N-(1-phenylethyl)-aminomethyl,N-methyl-N-(2-phenylethyl)-aminomethyl,N-(2-hydroxy-1-phenylethyl)-N-methylamino,N-(2-hydroxy-1-phenylethyl)-N-methyl-aminomethyl,N-(2-methoxy-1-phenylethyl)-N-methylamino,N-[2-(acetylamino-phenyl)ethyl]-N-methylamino,N-(furylmethyl)-N-methylamino, N-methyl-N-(thienylmethyl)-amino,N-benzyl-N-(2-hydroxyethyl-aminomethyl, N,N-bis(furylmethyl)-amino,3,3-dimethylpiperidinylmethyl, 2-phenylpiperidinyl,2-phenylpiperidinylmethyl, 3-hydroxy-2-phenylpiperidinylmethyl and1,2,3,4-tetrahydroisoquinolin-2-yl.

Particular values of R include benzyloxy,N-[1-(fluorophenyl)-2-hydroxyethyl]-amino and N-benzyl-N-methylamino.

Suitable values of R^(a) include hydrogen, hydroxy and benzyl,especially hydrogen.

Suitably, R² and R³ independently represent hydrogen or methyl,especially hydrogen.

Suitably, R⁴ represents hydrogen or methyl, especially hydrogen.

Suitably, R⁵ and R⁶ are independently selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl,phenyl, methylphenyl (especially 4-methylphenyl), benzyl and phenethyl.

Suitably, the substituent Z represents hydrogen, fluoro, cyano, hydroxy,methoxy, ethoxy, benzyloxy, methylamino-carbonyloxy, cyano-methoxy,aminocarbonyl-methoxy, methylsulphonyl, aminosulphonyl,N-methylamino-sulphonyl, N,N-dimethylamino-sulphonyl, amino,formylamino, acetylamino, trifluoromethyl-carbonylamino,benzyloxy-carbonylamino, methyl-sulphonylamino, ethyl-sulphonylamino,methylphenyl-sulphonylamino, N-methyl-(N-methylsulphonyl)-amino,N-methyl-(N-ethylsulphonyl)-amino,N-methyl-(N-trifluoromethylsulphonyl)-amino,N-ethyl-(N-methylsulphonyl)-amino, N-benzyl-(N-methylsulphonyl)-amino,N-benzyl-(N-ethylsulphonyl)-amino, acetyl, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,propylaminocarbonyl, butylaminocarbonyl, benzylaminocarbonyl orphenethyl-aminocarbonyl; or a group of formula (Za), (Zb), (Zc) or (Zd)as defined above; or an optionally substituted five-memberedheteroaromatic ring as specified above.

In a particular embodiment, Z represents --SO₂ NR⁵ R⁶ in which R⁵ and R⁶are as defined above. In a subset of this embodiment, R⁵ and R⁶independently represent hydrogen or C₁₋₆ alkyl, especially hydrogen ormethyl. Particular values of Z in this context include aminosulphonyl,N-methylamino-sulphonyl and N,N-dimethylamino-sulphonyl, especiallyN-methylamino-sulphonyl.

In another embodiment, Z represents a group of formula (Zb) in which R⁴is hydrogen or methyl. In a subset of this embodiment, X and Y bothrepresent oxygen. In a particular aspect of this subset, the chiralcentre denoted by the asterisk * is in the (S) configuration.

When the group Z represents an optionally substituted five-memberedheteroaromatic ring, this is suitably a 1,3-oxazole, 1,3-thiazole,imidazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring.Preferably, the ring is a 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole or 1,2,4-triazole ring, in particular a1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl moiety.

Suitably, the five-membered heteroaromatic ring Z is unsubstituted.Examples of optional substituents which may typically be attached to themoiety Z include methyl, ethyl, benzyl and amino.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof: ##STR7## wherein m is zero, 1, 2 or 3, preferably zero or 1;

p is zero, 1 or 2;

Q¹ represents a straight or branched alkylene chain containing from 2 to5 carbon atoms, substituted in any position by one or more fluorineatoms;

T represents nitrogen or CH;

A represents nitrogen or CH;

B represents nitrogen or C--R⁸ ;

R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₇ cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,heteroaryl, heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl;

R¹¹ represents --OR⁹ or --NR⁹ R¹⁰ ; and

R⁹ and R¹⁰ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl, aryl(C₁₋₆)alkyl, heteroarylor heteroaryl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted.

Examples of suitable optional substituents on the groups R⁹ and R¹⁰include C₁₋₆ alkyl, halogen, cyano, trifluoromethyl, hydroxy, C₁₋₆alkoxy, aminocarbonyloxy, C₂₋₆ alkylcarbonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, C₁₋₆ alkylsulphonylaminoand C₁₋₆ alkylaminosulphonylmethyl.

Representative values of R⁹ and R¹⁰ include hydrogen, methyl,hydroxyethyl, isobutyl, 2,2-dimethylpropyl, allyl, dimethylallyl,1-cyclohexylethyl, 2-cyclohexylethyl, indanyl, hydroxy-indanyl, phenyl,benzyl, methyl-benzyl, fluorobenzyl, methoxy-benzyl, acetylamino-benzyl,1-phenylethyl, 2-phenylethyl, 2-hydroxy-1-phenylethyl,2-methoxy-1-phenylethyl, 2-aminocarbonyloxy-1-phenylethyl,1-(fluorophenyl)ethyl, 1-(fluorophenyl)-2-hydroxyethyl,1-(fluorophenyl)-2-methoxyethyl, 1-(acetylamino-phenyl)ethyl,2-(acetylamino-phenyl)ethyl, 2-hydroxy-1-phenylprop-1-yl,1-phenylprop-2-yl, 2-phenylprop-2-yl, 1-hydroxy-1-phenylprop-2-yl,1-hydroxy-2-phenylprop-2-yl, 1-hydroxy-3-phenylprop-2-yl, furylmethyl,thienylmethyl and pyridylmethyl.

Particular values of R⁹ and R¹⁰ include hydrogen, methyl, benzyl and1-(fluorophenyl)-2-hydroxyethyl.

In relation to formula IIA, the variable p is preferably zero.

Suitably, Q¹ represents a straight or branched 3 or 4 carbon alkylenechain, substituted in any position by one or two fluorine atoms. Wherethe alkylene linkage Q¹ is substituted by two fluorine atoms, the gemdifluoro substitution pattern is preferred. Particular alkylene chainsfor Q¹ include 2-fluoropropylene, 2,2-difluoropropylene and2-(fluoromethyl)-propylene.

Particular values of R⁷ and R⁸ include hydrogen, methyl, ethyl, benzyland amino, especially hydrogen.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIB, and salts and prodrugs thereof:##STR8## wherein m, p, Q¹, T and R¹¹ are as defined with reference toformula IIA above; and

R⁵ and R⁶ are as defined with reference to formula I above.

Particular values of R⁵ and R⁶ in relation to formula IIB above includehydrogen and C₁₋₆ alkyl, especially hydrogen or methyl. Suitably, one ofR⁵ and R⁶ represents hydrogen and the other represents hydrogen ormethyl.

A further sub-class of compounds according to the invention isrepresented by the compounds of formula IIC, and salts and prodrugsthereof: ##STR9## wherein the asterisk * denotes a chiral centre; m, p,Q¹, T and R¹¹ are as defined with reference to formula IIA above; and

R⁴ and Y are as defined with reference to formula I above.

Particular values of R⁴ in relation to formula IIC include hydrogen andmethyl.

Preferably, Y in formula IIC is oxygen.

Preferably, the chiral centre denoted by the asterisk * in formula IICis in the (S) configuration.

In a particular aspect, the present invention provides compounds offormula IIA, IIB and IIC as defined above, and salts and prodrugsthereof, wherein R¹¹ represents a group of formula --NR⁹ R¹⁰ in which R⁹and R¹⁰ are as defined above.

Specific compounds within the scope of the present invention include:

4-(N-benzyl-N-methylamino)-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

4-[(R)-2-hydroxy-1-(4-fluorophenyl)ethylamino]-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

4-(N-benzyl-N-methylamino)-1-[2,2-difluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

4-benzyloxy-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

4-benzyloxy-1-[2,2-difluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of migraine, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds according to the invention wherein T represents CH, Urepresents C--R² and V represents N--R³, corresponding to the indolederivatives of formula IC as defined above wherein V represents N--R³,may be prepared by a process which comprises reacting a compound offormula III: ##STR10## wherein Z and E are as defined above; with acompound of formula IV, or a carbonyl-protected form thereof: ##STR11##wherein R², Q, M, R and R^(a) are as defined above; followed, whererequired, by N-alkylation by standard methods to introduce the moietyR³.

The reaction between compounds III and IV, which is an example of thewell-known Fischer indole synthesis, is suitably carried out by heatingthe reagents together under mildly acidic conditions, e.g. 4% sulphuricacid at reflux.

Suitable carbonyl-protected forms of the compounds of formula IV includethe dimethyl acetal or ketal derivatives.

The Fischer reaction between compounds III and IV may be carried out ina single step, or may proceed via an initial non-cyclising step at alower temperature to give an intermediate of formula V: ##STR12##wherein Z, E, Q, R², M, R and R^(a) are as defined above; followed bycyclisation using a suitable reagent, e.g. a polyphosphate ester.

The intermediates of formula IV, or carbonyl-protected forms thereof,may be prepared by procedures analogous to those described in theaccompanying Examples, or alternatively by reacting a compound offormula VI, or a carbonyl-protected form thereof, with a compound offormula VII: ##STR13## wherein Q, R², M, R and R^(a) are as definedabove, and L¹ represents a suitable leaving group.

The leaving group L¹ is suitably a halogen atom, e.g. chlorine orbromine.

Where L¹ represents a halogen atom, the reaction between compounds VIand VII is conveniently effected by stirring the reactants under basicconditions in a suitable solvent, for example sodium carbonate orpotassium carbonate in 1,2-dimethoxyethane or N,N-dimethyl-formamide, ortriethylamine in tetrahydrofuran or acetonitrile, optionally in thepresence of sodium iodide.

In an alternative procedure, the compounds according to the inventionmay be prepared by a process which comprises reacting a compound offormula VII as defined above with a compound of formula VIII: ##STR14##wherein Z, E, Q, T, U and V are as defined above, and L² represents asuitable leaving group.

The leaving group L² is suitably an alkylsulphonyloxy orarylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy),trifluoromethanesulphonyloxy (triflyloxy) or p-toluenesulphonyloxy(tosyloxy).

Where L² represents an alkylsulphonyloxy or arylsulphonyloxy group, thereaction between compounds VII and VIII is conveniently carried out in asuitable solvent such as isopropanol, 1,2-dimethoxy-ethane orN,N-dimethylformamide, typically in the presence of a base such assodium carbonate or potassium carbonate, optionally in the presence ofsodium iodide.

The intermediates of formula VIII may be prepared by methods analogousto those described in the accompanying Examples, or by standardprocedures well known from the art.

In one representative approach, the compounds of formula VIII wherein Tand U both represent CH, V represents NH and L² represents a mesyloxy ortosyloxy group may be prepared by reacting a compound of formula III asdefined above with a compound of formula IX: ##STR15## wherein Q and R²are as defined above, and R^(p) represents a hydroxy-protecting groupsuch as tert-butyldimethylsilyl; under conditions analogous to thosedescribed above for the reaction between compounds III and IV; withremoval of the hydroxy-protecting group R^(p) ; followed by mesylationor tosylation of the hydroxy-substituted indole derivative therebyobtained using standard procedures, e.g. treatment with mesyl or tosylchloride in the presence of a base such as triethylamine or pyridine.

In a further procedure, the compounds according to the invention whereinT represents CH, U represents nitrogen and V represents N--R³,corresponding to the indazole derivatives of formula ID as definedabove, may be prepared by a process which comprises cyclising a compoundof formula X: ##STR16## wherein Z, E, Q, M, R and R^(a) are as definedabove, and D¹ represents a readily displaceable group; followed, whererequired, by N-alkylation by standard methods to introduce the moietyR³.

The cyclisation of compound X is conveniently achieved in a suitableorganic solvent at an elevated temperature, for example in a mixture ofm-xylene and 2,6-lutidine at a temperature in the region of 140° C.

The readily displaceable group D¹ in the compounds of formula X suitablyrepresents a C₁₋₄ alkanoyloxy group, preferably acetoxy. Where D¹represents acetoxy, the desired compound of formula X may beconveniently prepared by treating a carbonyl compound of formula XI:##STR17## wherein Z, E, Q, M, R and R^(a) are as defined above; or aprotected derivative thereof, preferably the N-formyl protectedderivative; with hydroxylamine hydrochloride, advantageously in pyridineat the reflux temperature of the solvent; followed by acetylation withacetic anhydride, advantageously in the presence of a catalytic quantityof 4-dimethylaminopyridine, in dichloromethane at room temperature.

The N-formyl protected derivatives of the intermediates of formula XImay conveniently be prepared by ozonolysis of the corresponding indolederivative of formula XII: ##STR18## wherein Z, E, Q, M, R and R^(a) areas defined above; followed by a reductive work-up, advantageously usingdimethylsulphide.

The indole derivatives of formula XII may be prepared by methodsanalogous to those described in the accompanying Examples, or byprocedures well known from the art.

In a still further procedure, the compounds according to the inventionwherein T represents CH, U represents C--R² and V represents oxygen orsulphur, corresponding to the benzofuran or benzthiophene derivatives offormula IC wherein V is oxygen or sulphur respectively, may be preparedby a process which comprises cyclising a compound of formula XIII:##STR19## wherein Z, E, Q, R², M, R and R^(a) are as defined above, andV¹ represents oxygen or sulphur.

The cyclisation of compound XIII is conveniently effected by usingpolyphosphoric acid or a polyphosphate ester, advantageously at anelevated temperature.

The compounds of formula XIII may be prepared by reacting a compound offormula XIV with a compound of formula XV: ##STR20## wherein Z, E, Q,R², V¹, M, R and R^(a) are as defined above, and Hal represents ahalogen atom.

The reaction is conveniently effected in the presence of a base such assodium hydroxide.

The hydroxy and mercapto derivatives of formula XIV may be prepared by avariety of methods which will be readily apparent to those skilled inthe art. One such method is described in EP-A-0497512.

In a yet further procedure, the compounds according to the invention maybe prepared by a process which comprises reducing a compound of formulaXVI: ##STR21## wherein Z, E, T, U, V, M, R and R^(a) are as definedabove, and --Q² --CH₂ -- corresponds to the moiety Q as defined above.

The reaction is suitably carried out by treating the compound of formulaXVI with a reducing agent such as lithium aluminium hydride in anappropriate solvent, e.g. diethyl ether, tetrahydrofuran or mixturesthereof.

The compounds of formula XVI above may suitably be prepared by reactinga compound of formula VII as defined above with the appropriate compoundof formula XVII: ##STR22## wherein Z, E, T, U, V and Q² are as definedabove, and J represents a reactive carboxylate moiety.

Suitable values for the reactive carboxylate moiety J include esters,for example C₁₋₄ alkyl esters; acid anhydrides, for example mixedanhydrides with C₁₋₄ alkanoic acids; acid halides, for example acidchlorides; and acylimidazoles.

By way of example, the intermediates of formula XVII above wherein J isan acid chloride moiety may be prepared by treating the correspondingcarboxylic acid derivative with thionyl chloride in toluene. Similarly,the intermediates of formula XVII wherein J is an acylimidazole moietymay be prepared by treating the corresponding carboxylic acid derivativewith 1,1'-carbonyldiimidazole. Alternatively, the reactive carboxylatemoiety J may be obtained by treating the corresponding compound whereinJ is carboxy with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 1-hydroxybenzotriazole hydrate, optionally in thepresence of triethylamine; the resulting activated carboxylateintermediate may then suitably be reacted in situ with the requiredcompound of formula VII.

The hydrazine derivatives of formula III above may be prepared bymethods analogous to those described in WO-A-91/18897, WO-A-94/02477,EP-A-0438230, EP-A-0497512 and EP-A-0548813.

Where they are not commercially available, the starting materials offormula VI, VII, IX, XV and XVII may be prepared by the methodsdescribed in the accompanying Examples, or by analogous procedures whichwill be apparent to those skilled in the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. For example, a compound of formula I wherein R^(x) is benzylinitially obtained may be converted into a compound of formula I whereinR^(x) is hydrogen typically by conventional catalytic hydrogenation, orby transfer hydrogenation using a hydrogenation catalyst such aspalladium on charcoal in the presence of a hydrogen donor such asammonium formate. Moreover, a compound of formula I wherein R¹ ishydroxy initially obtained may be converted into the correspondingcarbonyl compound (aldehyde or ketone) by treatment with a conventionaloxidising agent such as sulphur trioxide-pyridine complex; the resultingcarbonyl compound may then be converted in turn into a compound offormula I wherein R¹ represents --NHR^(y), suitably by a standardreductive amination procedure which comprises treating the carbonylcompound with the appropriate amine of formula R^(y) --NH₂ in thepresence of a suitable reducing agent, typically sodiumcyanoborohydride. Alternatively, the carbonyl compound may be convertedinto a compound of formula I wherein R represents --CH₂ --SOR^(x) andR^(a) represents hydroxy by treatment of the carbonyl compound with theanion of CH₃ --SOR^(x). Furthermore, a compound of formula I wherein R¹represents --NHR^(y) initially obtained may be converted into a furthercompound of formula I wherein R¹ represents --NR^(x) R^(y), in whichR^(x) corresponds to the group --CH₂ R^(z), suitably by a reductiveamination procedure which comprises treating the compound of formula Iwherein R¹ represents --NHR^(y) with the appropriate aldehyde of formulaR^(z) --CHO in the presence of a reducing agent such as sodiumcyanoborohydride. In addition, a compound of formula I wherein R³ ishydrogen initially obtained may be converted into a compound of formulaI wherein R³ represents C₁₋₆ alkyl by standard alkylation techniques,for example by treatment with an alkyl iodide, e.g. methyl iodide,typically under basic conditions, e.g. sodium hydride inN,N-dimethylformamide.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with the present invention potently andselectively bind to the 5-HT_(1D)α receptor subtype, inhibitforskolin-stimulated adenylyl cyclase activity, and stimulate [³⁵S]-GTPγS binding to membranes from clonal cell lines expressing humancloned receptors.

5-HT_(1D)α /5-HT_(1D)β Radioligand Binding

Chinese hamster ovary (CHO) clonal cell lines expressing the human5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised in ice cold 50 mM Tris-HCl (pH 7.7 at room temperature) witha Kinematica polytron and centrifuged at 48,000 g at 4° C. for 11 min.The pellet was then resuspended in 50 mM Tris-HCl followed by a 10 minincubation at 37° C. Finally the tissue was recentrifuged at 48,000 g,4° C. for 11 min and the pellet resuspended, in assay buffer(composition in mM: Tris-HCl 50, pargyline 0.01, CaCl₂ 4; ascorbate0.1%; pH 7.7 at room temperature) to give the required volumeimmediately prior to use (0.2 mg protein/ml). Incubations were carriedout for 30 min at 37° C. in the presence of 0.02-150 nM [³ H]-5-HT forsaturation studies or 2-5 nM [³ H]-5-HT for displacement studies. Thefinal assay volume was 1 ml. 5-HT (10 μM) was used to definenon-specific binding. The reaction was initiated by the addition ofmembrane and was terminated by rapid filtration through Whatman GF/Bfilters (presoaked in 0.3% PEI/0.5% Triton X) followed by 2×4 mlwashings with 50 mM Tris-HCl. The radioactive filters were then countedon a LKB beta or a Wallac beta plate counter. Binding parameters weredetermined by non-linear, least squares regression analysis using aniterative curve fitting routine, from which IC₅₀ (the molarconcentration of compound necessary to inhibit binding by 50%) valuescould be calculated for each test compound. The IC₅₀ values for bindingto the 5-HT_(1D)α receptor subtype obtained for the compounds of theaccompanying Examples were below 50 nM in each case. Furthermore, thecompounds of the accompanying Examples were all found to possess aselective affinity for the 5-HT_(1D)α receptor subtype of at least10-fold relative to the 5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β Adenylyl Cyclase Assay

Studies were performed essentially as described in J. Pharmacol. Exp.Ther., 1986, 238, 248. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised, using a motor driven teflon/glass homogeniser, in ice coldTris HCl-EGTA buffer (composition in mM: Tris HCl 10, EGTA 1, pH 8.0 atroom temperature) and incubated on ice for 30-60 min. The tissue wasthen centrifuged at 20,000 g for 20 min at 4° C., the supernatantdiscarded and the pellet resuspended in Tris HCl-EDTA buffer(composition in mM: Tris HCl 50, EDTA 5, pH 7.6 at room temperature)just prior to assay. The adenylyl cyclase activity was determined bymeasuring the conversion of α-[³³ P]-ATP to [³³ P]-cyclic AMP. A 10 μlaliquot of the membrane suspension was incubated, for 10-15 min, in afinal volume of 50 μl, at 30° C., with or without forskolin (10 μM), inthe presence or absence of test compound. The incubation bufferconsisted of 50 mM Tris HCl (pH 7.6 at room temperature), 100 mM NaCl,30 μM GTP, 50 μM cyclic AMP, 1 mM dithiothreitol, 1 mM ATP, 5 mM MgCl₂,1 mM EGTA, 1 mM 3-isobutyl-1-methylxanthine, 3.5 mM creatininephosphate, 0.2 mg/ml creatine phosphokinase, 0.5-1 μCi α-[³³ P]-ATP and1 nCi [³ H]-cyclic AMP. The incubation was initiated by the addition ofmembrane, following a 5 min preincubation at 30° C., and was terminatedby the addition of 100 μl SDS (composition in mM: sodium lauryl sulphate2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature). The ATP andcyclic AMP were separated on a double column chromatography system(Anal. Biochem., 1974, 58, 541). Functional parameters were determinedusing a least squares curve fitting programme ALLFIT (Am. J. Physiol.,1978, 235, E97) from which E_(max) (maximal effect) and EC₅₀ (the molarconcentration of compound necessary to inhibit the maximal effect by50%) values were obtained for each test compound. Of those compoundswhich were tested in this assay, the EC₅₀ values for the 5-HT_(1D)αreceptor obtained for the compounds of the accompanying Examples werebelow 500 nM in each case. Moreover, the compounds of the accompanyingExamples which were tested were all found to possess at least a 10-foldselectivity for the 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β GTPγS Binding

Studies were performed essentially as described in Br. J. Pharmacol.,1993, 109, 1120. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised using a Kinematica polytron in ice cold 20 mM HEPEScontaining 10 mM EDTA, pH 7.4 at room temperature. The membranes werethen centrifuged at 40,000 g, 4° C. for 15 min. The pellet was thenresuspended in ice cold 20 mM HEPES containing 0.1 mM EDTA, pH 7.4 atroom temperature and recentrifuged at 40,000 g, 4° C. for 15-25 minutes.The membranes were then resuspended in assay buffer (composition in mM:HEPES 20, NaCl 100, MgCl₂ 10, pargyline 0.01; ascorbate 0.1%; pH 7.4 atroom temperature) at a concentration of 40 μg protein/ml for the5-HT_(1D)α receptor transfected cells and 40-50 μg protein/ml for the5-HT_(1D)β receptor transfected cells. The membrane suspension was thenincubated, in a volume of 1 ml, with GDP (100 μM for 5-HT_(1D)α receptortransfected cells, 30 μM for the 5-HT_(1D)β receptor transfected cells)and test compound at 30° C. for 20 min and then transferred to ice for afurther 15 min. [³⁵ S]-GTPγS was then added at a final concentration of100 pM and the samples incubated for 30 min at 30° C. The reaction wasinitiated by the addition of membrane and was terminated by rapidfiltration through Whatman GF/B filters and washed with 5 ml water. Theradioactive filters were then counted on a LKB beta counter. Functionalparameters were determined by a non-linear, least squares regressionanalysis using an iterative curve fitting routine, from which E_(max)(maximal effect) and EC₅₀ (the molar concentration of compound necessaryto inhibit the maximal effect by 50%) values were obtained for each testcompound. Of those compounds which were tested in this assay, the EC₅₀values for the 5-HT_(1D)α receptor obtained for the compounds of theaccompanying Examples were below 500 nM in each case. Moreover, thecompounds of the accompanying Examples which were tested were all foundto possess at least a 10-fold selectivity for the 5-HT_(1D)α receptorsubtype relative to the 5-HT_(1D)β subtype.

INTERMEDIATE 1

4-(1,2,4-Triazol-4-yl)phenylhydrazine

Prepared as described in WO 94/03446.

INTERMEDIATE 2

(R,S)-2-Fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propan-1-ol

a) (R,S)-2-Fluoro-5-hexen-1-ol

To a cooled (-10° C.) and stirred mixture of hydrogen fluoride-pyridine(70% HF; 10 ml) and anhydrous dichloromethane (60 ml), in apolypropylene tube, was added dropwise via syringe neat1,2-epoxy-5-hexene (13.8 ml) over 20 minutes, under nitrogen. After afurther 20 minutes, the yellow solution was carefully poured intoice-water-concentrated ammonia (57 ml of ammonia; total volume 400 ml)and the aqueous mixture was saturated with solid sodium chloride.Products were extracted with diethyl ether (2×500 ml) and the combinedethereal solutions were washed with brine (45 ml), brine--10% aqueoussodium bicarbonate (5:1, 60 ml), then dried (MgSO₄) and concentrated(bath temperature 30° C.). Flash chromatography of the residual liquid(silica gel, hexane-diethyl ether, 65:35), followed by purification onalumina (activity III, dichloromethane), gave 4.4 g of the titlecompound as a colourless liquid; δ_(H) (360 MHz, CDCl₃) 1.56-1.90 (2H,m), 2.10-2.30 (2H, m), 3.62-3.80 (2H, m), 4.48-4.70 (1H, dm, J=50 Hz),5.00-5.12 (2H, m), 5.75-5.88 (1H, m).

b) (R,S)-6-tert-Butyldimethylsilyloxy-5-fluoro-1-hexene

To a stirred solution of 2-fluoro-5-hexen-1-ol (4.4 g, 37.2 mmol) inanhydrous dimethylformamide (125 ml) were added imidazole (7.60 g, 111.7mmol) and tert-butyldimethylsilyl chloride (8.42 g, 55.9 mmol), undernitrogen. After being stirred at room temperature for 7.5 hours, themixture was diluted with diethyl ether (400 ml) and it was washed withwater (150 ml), 1M hydrochloric acid (100 ml), 5% aqueous sodiumbicarbonate (100 ml), brine (100 ml), then dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel, petrolether (40-60) to petrol ether (40-60)--5% diethyl ether) gave the titlecompound as a colourless liquid. Some impure fractions were repurifiedon alumina (activity III; petroleum ether (40-60)); total yield ofproduct 6.72 g (77.7%); δ_(H) (360 MHz, CDCl₃) 0.07 (6H, s), 0.90 (9H,s), 1.58-1.84 (2H, m), 2.10-2.30 (2H, m), 3.71 (2H, dd, J=22.2 and 4.7Hz), 4.40-4.60 (1H, dm, J=49 Hz), 4.96-5.10 (2H, m), 5.75-5.88 (1H, m).

c) (R,S)-5-tert-Butyldimethylsilyloxy-4-fluoropentanal

Ozone was bubbled through a cooled (-75° C.) and stirred solution of thepreceding olefin (6.7 g, 28.8 mmol) in anhydrous dichloromethane (150ml) until a blue colour persisted (45 minutes). Oxygen was then bubbledfor 10 minutes through the solution before it was kept under a nitrogenatmosphere. Anhydrous dimethyl sulfide (10 ml, 136.2 mmol) was added at-78° C. and the mixture was allowed to warm to room temperature. After 2hours, solvents were removed under vacuum (bath temperature 32° C.) andthe residue was purified by flash chromatography (silica gel,hexane-diethyl ether, 80:20) to give 5.45 g of the intermediate ozonideand 1 g of the required title product, as pale pink liquids. The ozonide(5.4 g, 19.28 mmol) in anhydrous dichloromethane (125 ml) was cooled to-78° C., under nitrogen, and anhydrous triethylamine (5.4 ml, 38.6 mmol)was added over 2 minutes. The resulting solution was allowed to warm toroom temperature and stirred for 2.5 hours. The mixture was halfconcentrated under vacuum and directly chromatographed on silica gel(dichloromethane) to give 3.60 g of the title compound as a colourlessliquid; δ_(H) (360 MHz, CDCl₃) 0.07 (6H, s), 0.90 (9H, s), 1.90-2.05(2H, m), 2.54-2.72 (2H, m), 3.73 (2H, dd, J=21.3 and 4.5 Hz), 4.40-4.62(1H, (dm, J=49.5 Hz), 9.81 (1H, dd, J=2.1 and 0.9 Hz).

d) (R,S)-2-Fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propan-1-ol

To a stirred solution of the preceding aldehyde (4.60 g, 19.6 mmol) indioxane (170 ml) was added 4-(1,2,4-triazol-4-yl)phenylhydrazine (3.80g, 21.1 mmol) followed by water (20 ml). After 15 minutes, 2Mhydrochloric acid (11 ml) was added and the mixture was refluxed for 68hours under nitrogen. Solvents were removed under vacuum and the residuewas purified by flash chromatography (silica gel,dichloromethane-methanol, 90:10), then alumina (activity III,dichloromethane-methanol-ammonia, 95:5:0.5; thendichloromethane-methanol-ammonia, 90:10:1), to give 700 mg of the titlecompound as a yellow solid; δ_(H) (360 MHz, DMSO-₆) 2.98-3.10 (2H, m),3.44-3.66 (2H, m), 4.66-4.88 (1H, dm, J=49 Hz), 4.93 (1H, t, J=5.6 Hz),7.32 (1H, dd, J=8.5 and 1.9 Hz), 7.35 (1H, d, J=2.1 Hz), 7.50 (1H, d,J=8.5 Hz), 7.82 (1H, d, J=1.9 Hz), 9.00 (2H, s), 11.19 (1H, s); m/e (ES)261 (M⁺ +1).

EXAMPLE 1

4-(N-Benzyl-N-methylamino)-1-{(R,S)-2-fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine.2.25 Hydrogen Oxalate. 1.0 Hydrate

a) 1-tert-Butyloxycarbonyl-4-N-benzyl-N-methylamino)piperidine

To a stirred solution of 1-tert-butyloxycarbonyl-4-piperidone (3.30 g,16.5 mmol) and benzylamine (1.64 ml, 15.0 mmol) in a mixture of methanol(150 ml) and glacial acetic acid (3.4 ml, 60 mmol) was added sodiumcyanoborohydride (1.04 g, 16.5 mmol), and the resulting mixture wasstirred at room temperature for 2 hours 15 minutes. A solution offormaldehyde (38% w/v aqueous solution; 1.42 ml) in methanol (5 ml) wasadded and stirring was continued for 16 hours. 4N Sodium hydroxide (35ml) was added and the methanol was removed under vacuum. The residue wasdiluted with water (50 ml) and products were extracted with diethylether (2×300 ml). The combined organic phases were washed with brine (50ml), dried (Na₂ SO₄) and concentrated. Flash chromatography of theresidue (silica gel, dichloromethane-methanol-ammonia, 97:3:0.2)followed by repurification of impure fractions on alumina (activity III,dichloromethane) afforded 3.98 g (87.4%) of the title compound as acolourless thick oil; δ_(H) (360 MHz, CDCl₃) 1.46 (9H, s), 1.44-1.56(2H, m), 1.76-1.85 (2H, m), 2.20 (3H, s), 2.52-2.76 (3H, m), 3.57 (2H,s), 4.10-4.22 (2H, m), 7.20-7.36 (5H, m); m/e (ES) 305 (M⁺ +1).

b) 4-(N-Benzyl-N-methylamino)piperidine

A solution of the preceding piperidine (3.95 g, 12.97 mmol) in a mixtureof dichloromethane (40 ml) and trifluoroacetic acid (40 ml) was allowedto stand at room temperature for 3 hours. Solvents were removed undervacuum and the residue azeotroped with toluene-methanol (5:1, 100 ml).The remaining residue was dissolved in 4N sodium hydroxide (50 ml) andextracted with dichloromethane (2×50 ml). The combined organic solutionswere washed with brine (50 ml), dried (Na₂ SO₄) and concentrated to givethe title compound (2.70 g, 100%) which was used in the next stepwithout further purification; δ_(H) (360 MHz, CDCl₃) 1.52 (2H, dq,J=12.2 and 4.0 Hz), 1.80-1.90 (2H, m), 2.21 (3H, s), 2.50-2.66 (3H, m),3.12-3.22 (2H, m), 3.58 (2H, s), 7.18-7.36 (5H, m); m/e (ES) 205 (M⁺+1).

c)4-(N-Benzyl-N-methylamino)-1-{(R,S)-2-fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine.2.25 Hydrogen Oxalate. 1.0 Hydrate

To a stirred suspension of Intermediate 2 (200 mg, 0.77 mmol) inanhydrous tetrahydrofuran (30 ml) was added anhydrous triethylamine (214μl, 1.54 mmol) followed by methanesulphonyl chloride (121 μl, 1.54mmol). After being stirred at room temperature for 2 hours 10 minutes,under nitrogen, the mixture was diluted with ethyl acetate (125 ml),washed with brine-water (1:1, 25 ml), brine (25 ml), then dried (MgSO₄)and concentrated.

A mixture of the mesylate thus obtained, anhydrous potassium carbonate(128 mg) and 4-(N-benzyl-N-methylamino)piperidine (800 mg) inisopropanol (35 ml) was refluxed, under nitrogen, for 65 hours. Solventswere removed under vacuum, the residue was dissolved in water (40 ml)and products were extracted with ethyl acetate (2×100 ml). The combinedorganic solutions were washed with brine (1×40 ml), dried (Na₂ SO₄) andconcentrated. Flash chromatography of the residue (silica gel,dichloromethane-methanol-ammonia, 95:5:0.5) followed by purification onalumina (activity III, dichloromethane-methanol-ammonia, 97:3:0.2), andfinally flash chromatography (silica gel, dichloromethane-methanol,80:20) gave 188 mg (54.8%) of the title compound free base. The oxalatesalt was prepared from ethanol-diethyl ether, mp 110-117° C. (Found: C,54.81; H, 5.75; N, 12.55. C₂₆ H₃₁ FN₆ ×2.25C₂ H₂ O₄ ×1.0H₂ O requires:C, 54.91; H, 5.67; N, 12.60%). δ_(H) (360 MHz, D₂ O) 2.08-2.24 (2H, m),2.36-2.48 (2H, m), 2.75 (3H, s), 3.10-3.34 (4H, m), 3.38-3.58 (2H, m),3.62-3.92 (3H, m), 4.28-4.50 (2H, m), 5.26-5.48 (1H, m), 7.32 (1H, d,J=8.7 Hz), 7.40-7.55 (6H, m), 7.62 (1H, d, J=8.7 Hz), 7.77 (1H, s), 8.92(2H, s); m/e (ES) 447 M⁺ +1).

EXAMPLE 2

1-{(R,S)-2-Fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}-4-{[(R)-2-hydroxy-1-(4-fluorophenyl)ethyl]amino}piperidine.2.0 Hydrogen Oxalate. 1.2 Hydrate.

a) (R)-2-Amino-2-(4-fluorophenyl)ethanol

To a stirred 1.0M solution of lithium aluminium hydride in THF (23.5 ml,23.5 mmol), cooled to 0° C. under Ar, was added portionwise over 1 h 45min solid (-)-4-fluoro-D-α-phenylglycine (1.98 g, 11.7 mmol). Thereaction mixture was then stirred at room temperature overnight beforecarefully adding water (0.89 ml), then 4N NaOH solution (0.89 ml) andthen water (2.68 ml). The mixture was stirred for a few minutes, thenfiltered, and the filtrate was evaporated in vacuo. Flash chromatographyof the residue (silica gel, dichloromethane-methanol-ammonia, 90:10:1)gave 1.499 g (82%) of the title compound as a white solid; δ_(H) (250MHz, CDCl₃) 3.52 (1H, dd, J=10.7 and 8.2 Hz), 3.71 (1H, dd, J=10.7 and4.4 Hz), 4.06 (1H, dd, J=8.1 and 4.4 Hz), 6.99-7.08 (2H, m), 7.28-7.34(2H, m).

b)1-tert-Butyloxycarbonyl-4-{[(R)-2-hydroxy-1-(4-fluorophenyl)ethyl]amino}piperidine

To a stirred solution of 1-tert-butyloxycarbonyl-4-piperidone (3.30 g,16.5 mmol) and (R)-2-amino-2-(4-fluorophenyl)ethanol (2.33 g, 15.0 mmol)in a mixture of methanol (150 ml) and glacial acetic acid (3.4 ml, 60mmol) was added sodium cyanoborohydride (1.04 g, 16.6 mmol), and theresulting mixture was stirred at room temperature for 18.5 hours. 4NSodium hydroxide (30 ml) was added and the methanol was removed undervacuum. The remaining residue was diluted with water (50 ml) andproducts were extracted with diethyl ether (2×300 ml). The combinedethereal phases were washed with brine (50 ml), dried (Na₂ SO₄) andconcentrated. Flash chromatography of the residue (silica gel,dichloromethane-methanol-ammonia, 95:5:0.5) gave 4.60 g (90.7%) of thetitle compound as a thick oil which solidified on standing; δ_(H) (360MHz, CDCl₃) 1.16-1.30 (2H, m), 1.44 (9H, s), 1.58-1.68 (1H, m),1.84-1.92 (1H, m), 2.48-2.58 (1H, m), 2.66-2.78 (2H, m), 3.45 (1H, dd,J=10.7 and 8.7 Hz), 3.65 (1H, dd, J=10.7 and 4.5 Hz), 3.90-4.04 (3H, m),7.00-7.08 (2H, m), 7.22-7.30 (2H, m); m/e (ES) 339 (M⁺ +1).

c) 4-{[(R)-2-Hydroxy-1-(4-fluorophenyl)ethyl]amino}piperidine

The title compound was prepared form the product of the preceding stepusing a similar method to that described for Example 1, Step b. δ_(H)(360 MHz, CDCl₃ +DMSO-d₆) 0.90-1.04 (2H, m), 1.38-1.48 (1H, m),1.68-1.78 (1H, m), 2.12-2.32 (3H, m), 2.72-2.85 (2H, m), 3.23 (1H, dd,J=10.6 and 8.6 Hz), 3.40 (1H, dd, J=10.6 and 4.2 Hz), 3.75 (1H, dd,J=8.6 and 4.2 Hz), 6.74-6.82 (2H, m), 7.17-7.45 (2H, m); m/e (ES) 239(M⁺ +1).

d)1-{(R,S)-2-Fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}-4-{[(R)-2-hydroxy-1-(4-fluorophenyl)ethyl]amino}piperidine.2.0 Hydrozen Oxalate. 1.2 Hydrate

The title compound free base was prepared from the product of thepreceding step and Intermediate 2, following a similar procedure to thatdescribed for Example 1, step c. The oxalate salt was prepared fromethanol-diethyl ether, mp 130-140° C. (Found: C, 52.77; H, 5.60; N,12.31. C₂₆ H₃₀ F₂ N₆ O×2.0C₂ H₂ O₄ ×1.2H₂ O requires: C, 52.82; H, 5.38;N, 12.32%). δ_(H) (360 MHz, DMSO-d₆) 1.56-1.78 (2H, m), 1.86-2.04 (2H,m), 2.08-2.32 (2H, m), 2.64-2.82 (3H, m), 2.96-3.10 (4H, m), 3.71 (2H,d, J=5.6 Hz), 4.36 (1H, m), 4.96-5.18 (1H, m), 7.22-7.36 (4H, m), 7.50(1H, d, J=8.6 Hz), 7.56-7.60 (2H, m), 7.80 (1H, s), 9.00 (2H, s), 11.26(1H, s); m/e (ES) 481 (M⁺ +1).

EXAMPLE 3

4-(N-Benzyl-N-methylamino)-1-{2,2-difluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine

a) A solution of hexamethylene tetramine (12 g) and5-(1,2,4-triazol-4-yl)-1H-indole (10.5 g, 57.1 mmol) in acetic acid (125ml, 30% v/v) were heated at reflux for 3 hours. The reaction wasneutralized with potassium carbonate and the water removed in vacuo. Theresidue was triturated with water and the solid collected to give5-(1,2,4-triazol-4-yl)-3-(carboxaldehyde)-1H-indole as a brown solid.m/e (ES) 213 (M⁺ +1).

b) A suspension of the product from above (1.01 g, 4.8 mmol),N,N-dimethylaminopyridine (DMAP) (47 mg) and di-tert-butyldicarbonate(1.03 g), in 25 ml dichloromethane, was stirred for 8 hours. Furtherquantities of DMAP (50 mg) and di-tert-butyldicarbonate (200 mg) wereadded after 1.5 hours. The reaction was concentrated, and the solidtriturated with methanol, to give5-(1,2,4-triazol-4-yl)-3-(carboxaldehyde)-1-(tert-butoxycarbonyl)indoleas a beige solid. δ_(H) (250 MHz, d₆ -DMSO) 1.90 (9H, s), 7.96-8.00 (1H,m), 8.46 (1H, d, J=10 Hz), 8.54 (1H, d, J=3 Hz), 9.03 (1H, s), 9.38 (2H,s), 10.34 (1H, s). m/e (ES) 313 (M⁺ +1).

c) A suspension of activated zinc dust (85 mg) and the aldehyde fromabove (312 mg, 1 mmol) in 3 ml THF and 5 drops DMF was heated to refluxunder a nitrogen atmosphere. Ethyl bromodifluoroacetate (0.14 ml, 1.1mmol) was added. After 15 minutes, a further 0.5 eq of ethylbromodifluoroacetate was added, followed after 15 minutes by phenylchlorothionoformate (0.18 ml, 1.3 mmol). The reaction was heated atreflux 1.5 hours, and partitioned betwen water-ethyl acetate. Thecombined organic phases were separated, dried (MgSO₄), concentrated andchromatographed using 5% methanol-dichloromethane. The partiallypurified product was heated to reflux in 15 ml degassed toluene withtributyl tin hydride (0.27 ml, 1 mmol) and α,α'-azobisisobutyronitrile(118 mg). After 2.5 hours, the reaction was concentrated, andchromatographed using 2→5% methanol-dichloromethane. Ethyl2,2-difluoro-3-[5-(1,2,4-triazol-4-yl)-1-tert-butoxycarbonylindol-3-yl]propanoatewas obtained as a yellow oil. m/e (ES) 421 (M⁺ +1). δ_(H) (250 MHz,CDCl₃) 0.92 (3H, t, J=7.5 Hz), 1.69 (9H, s), 3.49 (2H, t, J=15 Hz), 4.28(2H, q, J=7.5 Hz), 7.30-7.35 (1H, m), 7.56 (1H, m), 7.67 (1H, s),8.30-8.34 (1H, m), 8.50 (2H, s).

d) A solution of the product from above (179 mg, 0.4 mmol) in 3 mlethanol was treated with sodium borohydride (20 mg) and the reactionmonitored. When all the starting material had reacted, the reaction wasquenched by addition of water. The ethanol was removed in vacuo, and theproduct extracted with ethyl acetate. The organic phase was dried(MgSO₄), concentrated and chromatographed using 5%methanol-dichloromethane as eluent.2,2-Difluoro-3-[5-(1,2,4-triazol-4-yl)-1-tert-butoxycarbonylindol-3-yl]propan-1-olwas obtained as a yellow oil. m/e (ES) 379 (M⁺ +1). δ_(H) (250 MHz,CDCl₃) 1.69 (9H, s), 3.42 (2H, t, J=17.5 Hz), 3.77 (2H, t, J=12.5 Hz),7.30-7.34 (1H, m), 7.69 (1H, s), 7.74 (1H, s), 8.29-8.32 (1H, m), 8.60(2H, br s).

e) A solution of the product from above (80 mg, 0.21 mmol) in 10 mlanhydrous dichloromethane and pyridine (70 μl) was cooled to an internaltemperature of -50° C. under a nitrogen atmosphere.Trifluoromethanesulfonic anhydride (71 μl) was added, and the reactionallowed to stir at -25→-50° C. for 1.5 h. Five ml of water was added,and the reaction allowed to attain room temperature. The organic phasewas separated, dried (MgSO₄), and concentrated. The crude triflate wasdissolved in 3 ml anhydrous DMF and heated 120° C. for 10 minutes withpotassium carbonate (58 mg) and the amine from Example 1, step b (86mg). The reaction was partitioned between ethyl acetate and water. Theorganic phase was separated, dried (MgSO₄) and concentrated, thendeprotected as described in Example 1, step b.

The title compound free base was obtained by chromatography using 3%methanol-dichloromethane→methanol-dichloromethane-ammonia (5:94:1). Thesalt was prepared as described in Example 1, step c. mp. softens at 85°C. δ_(H) (360 MHz, d₆ -DMSO) 1.66-1.80 (2H, m), 1.90-2.00 (2H, m),2.16-2.24 (2H, m), 2.54 (3H, s), 2.70 (2H, t, J=14.4 Hz), 2.90-3.00 (2H,m), 3.06-3.20 (1H, m), 3.44 (2H, t, J=14.4 Hz), 4.20-4.28 (2H, m),7.32-7.60 (8H, m), 7.84 (1H, s), 9.0 (2H, s), 11.4 (1H, s). m/e (ES) 465(M⁺ +1).

EXAMPLE 4

4-Benzyloxy-1-{(R,S)-2-fluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidineHydrogen Oxalate

4-Benzyloxypiperidine (0.88 g, 4.62 mmol) (Example 5, step b) wasreacted as described in Example 1, step c to give the title compound,mp. softens at 130° C. (Found: C, 60.13; H, 5.87; N, 12.42. C₂₅ H₂₈FNSO. C₂ H₂ O₄ requires C, 61.94; H, 5.76; N, 13.38). δ_(H) (360 MHz, d₆-DMSO) 1.60-1.80 (2H, m), 1.80-2.00 (2H, m), 2.54-2.70 (2H, m),2.80-3.20 (6H, m), 3.46-3.78 (1H, m), 4.50 (2H, s), 5.00-5.24 (1H, m),7.20-7.40 (7H, m), 7.46-7.56 (1H, m), 7.78 (1H, s), 8.87 (2H, s), 11.04(1H, s). m/e (ES) 434 (M⁺ +1).

EXAMPLE 5

4-Benzyloxy-1-{2,2-difluoro-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine

a) A solution of N-tert-butoxycarbonylpiperidin-4-ol (25 g, 0.124 mol)in 100 ml anhydrous THF was added to a suspension of sodium hydride(5.96 g, 0.15 mol, pentane washed) in 100 ml anhydrous THF at 0° C. Thereaction was stirred at 0° C. for 1 hour, then treated with a solutionof benzyl bromide (25.65 g, 0.15 mol) in 20 ml anhydrous THF. Thereaction was allowed to stand for 20 h at room temperature, cooled to 0°C., and 50 ml water was added cautiously. The product was extractedusing ethyl acetate, the combined organic extracts were washed withwater, dried (MgSO₄) and concentrated. Chromatography using petroleumether→20% ethyl acetate-petroleum ether gave4-benzyloxy-1-tert-butoxycarbonyl-piperidine as a colourless solid.δ_(H) (250 MHz, CDCl₃) 1.45 (9H, s), 1.51-1.65 (2H, m), 1.80-1.94 (2H,m), 3.04-3.15 (2H, m), 3.51-3.61 (1H, m), 3.70-3.84 (2H, m), 4.56 (2H,m), 7.26-7.35 (5H, m). m/e (ES) 292.

b) The product from above (6.1 g, 21 mmol) was reacted as described inExample 1, step b to give 4-benzyloxypiperidine as a crystalline solid.δ_(H) (360 MHz, CDCl₃) 1.43-1.57 (2H, m), 1.91-2.09 (2H, m), 2.55-2.66(2H, m), 3.06-3.15 (2H, m), 3.41-3.52 (1H, m), 4.56 (2H, s), 7.12-7.37(5H, m). m/e (ES) 192 (M⁺ +1).

c) Ethyl bromodifluoroacetate (32.07 g, 0.158 mol) and4-benzyloxy-piperidine (27.36 g) were stirred at room temperature inethanol overnight. Ethanol and excess reagents were removed in vacuo andthe residue was chromatographed using 10% ethyl acetate-petroleum etheras eluent to give1-(2-bromo-2,2-difluoroacetamido)-4-benzyloxypiperidine. δ_(H) (250 MHz,CDCl₃) 1.54-1.92 (4H, m), 3.60-3.87 (5H, m), 4.56 (2H, s), 7.25-7.38(5H, m).

d) A solution of allyltributyl tin (17.7 ml) and the product from above(19.9 g, 0.057 mol) in 200 ml of degassed toluene was heated to refluxunder a nitrogen atmosphere in the presence ofα,α'-azobisisobutyronitrile (0.5 g) for 48 h. Further aliquots of AIBNwere added, and refluxing was continued until the reaction had gone tocompletion. The reaction was concentrated and chromatographed using 5%ethyl acetate-petroleum ether to give1-(2,2-difluoro-4-pentenamido)-4-benzyloxypiperidine. δ_(H) (360 MHz,CDCl₃) 1.72-1.76 (2H, m), 1.86-1.91 (2H, m), 2.85-2.97 (2H, dt, J=18 and7.2 Hz), 3.44-3.60 (2H, m), 3.67-3.71 (1H, m), 3.80-3.96 (2H, m), 4.56(2H, s), 5.23 (1H, s), 5.26 (1H, d, J=7.2 Hz), 5.81-5.92 (1H, m),7.25-7.35 (5H, m). m/s (ES) 310 (M⁺ +1).

e) A solution of the product from above (7.0 g, 0.023 mol) in 20 mlanhydrous THF was treated with 9-BBN (182 ml of 0.5M solution) and washeated to reflux for 8 h. The reaction was cooled, and carefullybasified to pH11-12 using 4N NaOH. Hydrogen peroxide (30% w/v solution,7.82 g, 26 ml) was added slowly to the cooled reaction. The reaction wasallowed to stand for 18 h, adjusted to pH8-9, poured into water, andextracted with diethyl ether. The organic extracts were washed withbrine, water, dried (MgSO₄) and concentrated in vacuo. Purification bychromatography using 10% ethyl acetate petroleum ether as eluent gave1-(2,2-difluoro-5-hydroxypentan-1-yl)-4-benzyloxypiperidine as a paleyellow oil. δ_(H) (250 MHz, CDCl₃) 1.60-2.20 (8H, m), 1.36-2.54 (2H, m),2.70 (2H, t, J=15 Hz), 2.84-3.00 (2H, m), 3.40-3.54 (1H, m), 3.68 (2H,t, J=5 Hz), 4.53 (2H, s), 7.26-7.35 (5H, m). m/s (ES) 314 (M⁺ +1).

f) A solution of the product from above (3.3 g) in 20 ml anhydrousdimethylsulphoxide was stirred with triethylamine (10.35 ml) at 0° C.under a nitrogen atmosphere. Sulphur trioxide-pyridine (2.51 g) wasadded in portions. The reaction was stirred at room temperature for 11/2hours, a further portion of SO₃ -pyridine (0.2 g) added, and stirringcontinued for 45 minutes. Water was added carefully, the productextracted into ethyl acetate, the organic phase washed with brine, dried(MgSO₄), concentrated and purified by dry flash column chromatographyusing 10% ethyl acetate-petroleum ether as eluent.1-(2,2-Difluoro-5-pentanal)-4-benzyloxypiperidine was obtained as a paleyellow oil. δ_(H) (250 MHz, CDCl₃) 1.60-1.80 (2H, m), 1.84-2.00 (2H, m),2.20-2.46 (6H, m), 2.64-2.94 (4H, m), 3.44 (br s, 1H), 4.53 (2H, s),7.24-7.38 (5H, s), 9.90 (br s, 1H). m/e (ES) 312 (M⁺ +1).

g) The product from above was reacted in a similar manner as describedfor Intermediate 2 step d, using 4% sulfuric acid instead ofdioxane-water, to give the title compound free base. mp. 169.5-170.3° C.(ethanol). (Found: C, 66.14; H, 6.09; N, 15.31. C₂₅ H₂₇ F₂ N₅ O requiresC, 66.50; H, 6.05; N, 15.51). δ_(H) (360 MHz, d₆ -DMSO) 1.49-1.52 (2H,m), 1.80-1.90 (2H, m), 2.22-2.32 (2H, m), 2.60-2.78 (4H, m), 3.31-3.45(3H, m), 7.26-7.38 (7H, m), 7.50-7.52 (1H, m), 7.81 (1H, s), 8.98 (2H,s), 11.32 (1H, s). m/e (ES) 452 (M⁺ +1).

We claim:
 1. A compound of formula I, or a salt or prodrug thereof:##STR23## wherein Z represents hydrogen, halogen, cyano, nitro,trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂ CONR⁵R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group offormula (Za), (Zb), (Zc) or (Zd): ##STR24## in which the asterisk *denotes a chiral centre; or Z represents an optionally substitutedfive-membered heteroaromatic ring selected from furan, thiophene,pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole,oxadiazole, thiadiazole, triazole and tetrazole;X represents oxygen,sulphur, --NH-- or methylene; Y represents oxygen or sulphur; Erepresents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms; Q represents a straight or branchedalkylene chain containing from 1 to 6 carbon atoms, substituted in anyposition by one or more fluorine atoms; T represents CH; U representsC--R² ; V represents N--R³ ; R², R³ and R⁴ independently representhydrogen or C₁₋₆ alkyl; R⁵ and R⁶ independently represent hydrogen, C₁₋₆alkyl, trifluoromethyl, phenyl, methylphenyl, or an optionallysubstituted aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl group; or R⁵ andR⁶, when linked through a nitrogen atom, together represent the residueof an optionally substituted azetidine, pyrrolidine, piperidine,morpholine or piperazine ring; M represents the residue of a piperidinering; R represents a group of formula --W--R¹ ; W represents a chemicalbond or a straight or branched alkylene chain containing from 1 to 4carbon atoms, optionally substituted in any position by a hydroxy group;R¹ represents --OR^(x), --SR^(x), --SOR^(x), --SO₂ R^(x) or --NR^(x)R^(y) ; R^(x) and R^(y) independently represent hydrogen, hydrocarbon ora heterocyclic group; or R^(x) and R^(y) together represent a C₂₋₆alkylene group, which alkylene group may be optionally substituted byone or more substituents selected from C₁₋₆ alkyl, aryl and hydroxy, orfused with a phenyl ring; and R^(a) represents hydrogen, hydroxy,hydrocarbon or a heterocyclic group.
 2. A compound as claimed in claim 1represented by formula IIA, and salts and prodrugs thereof: ##STR25##wherein m is zero, 1, 2 or 3;p is zero, 1 or 2; Q¹ represents a straightor branched alkylene chain containing from 2 to 5 carbon atoms,substituted in any position by one or more fluorine atoms; T representsCH; A represents nitrogen or CH; B represents nitrogen or C--R⁸ ; R⁷ andR⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, heteroaryl,heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl; R¹¹represents --OR⁹ or --NR⁹ R¹⁰ ; and R⁹ and R¹⁰ independently representhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl,aryl, aryl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any of whichgroups may be optionally substituted.
 3. A compound as claimed in claim1 represented by formula IIB, and salts and prodrugs thereof: ##STR26##wherein m, p, Q¹, T and R¹¹ are as defined in claim 2; andR⁵ and R⁶ areas defined in claim
 1. 4. A compound as claimed in claim 1 representedby formula IIC, and salts and prodrugs thereof: ##STR27## wherein theasterisk * denotes a chiral centre; m, p, Q¹, T and R¹¹ are as definedin claim 2; andR⁴ and Y are as defined in claim
 1. 5. A compound asclaimed in claim 2 wherein R¹¹ represents a group of formula --NR⁹ R¹⁰.6. A compound selectedfrom:4-(N-benzyl-N-methylamino)-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;4-[(R)-2-hydroxy-1-(4-fluorophenyl)ethylamino]-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;andsalts and prodrugs thereof.
 7. A compound selectedfrom:4-(N-benzyl-N-methylamino)-1-[2,2-difluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;4-benzyloxy-1-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;4-benzyloxy-1-[2,2-difluoro-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;andsalts and prodrugs thereof.
 8. A pharmaceutical composition comprisingan effective amount of a compound of formula I as defined in claim 1 ora pharmaceutically acceptable salt thereof or a prodrug thereof inassociation with a pharmaceutically acceptable carrier.
 9. A process forthe preparation of a compound as claimed in claim 1, which comprises:(A)reacting a compound of formula III: ##STR28## wherein Z and E are asdefined in claim 1; with a compound of formula IV, or acarbonyl-protected form thereof: ##STR29## wherein R², Q, M, R and R^(a)are as defined in claim 1; followed, where required, by N-alkylation bystandard methods to introduce the moiety R³ ; or (B) reacting a compoundof formula VII: ##STR30## wherein R and R^(a) are as defined in claim 1;with a compound of formula VIII: ##STR31## wherein Z, E, Q, T, U and Vare as defined in claim 1, and L² represents a suitable leaving group;or (C) cyclising a compound of formula X: ##STR32## wherein Z, E, Q, M,R and R^(a) are as defined in claim 1, and D¹ represents a readilydisplaceable group; followed, where required, by N-alkylation bystandard methods to introduce the moiety R³ ; or (D) cyclising acompound of formula XIII: ##STR33## wherein Z, E, Q, R², M, R and R^(a)are as defined in claim 1, and V¹ represents oxygen or sulphur; or (E)reducing a compound of formula XVI: ##STR34## wherein Z, E, T, U, V, M,R and R^(a) are as defined in claim 1, and --Q² --CH₂ -- corresponds tothe moiety Q as defined in claim
 1. 10. A compound as claimed in claim 3wherein R¹¹ represents a group of formula --NR⁹ R¹⁰.
 11. A compound asclaimed in claim 4 wherein R¹¹ represents a group of formula --NR⁹ R¹⁰.